[Complex management of type 2 heparin-induced thrombocytopenia in patients with major bleeding tendency: two case report]. / Prise en charge de la thrombopénie induite par l'héparine immuno-allergique de type 2 au travers de deux cas cliniques chez des patients à risque hémorragique majeur.

Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.

High-dose intravenous immunoglobulin to treat spontaneous heparin-induced thrombocytopenia syndrome.

Essentials Spontaneous HIT syndrome clinically/serologically resembles HIT but without proximate heparin. Rarely, spontaneous HIT syndrome complicates total knee arthroplasty surgery. Mesenteric vein thrombosis is a rare presentation of spontaneous HIT syndrome. IVIg rapidly corrects thrombocytopenia by inhibiting heparin-independent platelet activation. SUMMARY: Spontaneous heparin-induced thrombocytopenia (HIT) syndrome is an autoimmune HIT (aHIT) disorder characterized by thrombocytopenia, thrombosis, and HIT antibodies despite no proximate heparin exposure. For unknown reasons, many cases occur after total knee arthroplasty. A 52-year-old woman presented 12 days posttotal knee replacement (aspirin thromboprophylaxis) with gastrointestinal bleeding (superior mesenteric vein thrombosis); the platelet count was 63 × 109 L-1 . After bowel resection and a brief course of heparin, treatment was changed to argatroban followed by fondaparinux. In addition, high-dose intravenous immunoglobulin (IVIg), 1 g kg-1 on 2 consecutive days, resulted in abrupt platelet count rise from 21 (nadir) pre-IVIg to 137 (post-IVIg), and 2 days later to 200 × 109 L-1 . Heparin-independent serum-induced serotonin-release abruptly decreased from 91% (pre-IVIg) to 14% (post-IVIg); although serotonin-release later rebounded to 49%, the patient's platelet counts remained normal. Our observations support the emerging concept that high-dose IVIg is effective for treating aHIT disorders, including spontaneous HIT syndrome.

In vitro effects of a kaolin-coated hemostatic dressing on anticoagulated blood.

BACKGROUND: The use of kaolin-coated dressings has become common and have efficacy in normal patients, but their increased use will inevitably include use on bleeding patients taking anticoagulants. We hypothesize that kaolin coating material (KCM) will improve clotting regardless of anticoagulation medication. METHODS: A prospective study was performed on blood from patients who were on a vitamin K antagonist (VKA), unfractionated heparin (UH), an antiplatelet (AP) agent, a Xa inhibitor (Xa), or a direct thrombin inhibitor (DTI). None were on more than one type of anticoagulation medication. Viscoelastic testing was performed with and without KCM. All p values were adjusted for multiple comparisons. RESULTS: The addition of KCM significantly decreased the time for initial clot formation (CT) in all groups. The mean CT for controls was decreased from 692 to 190.8 s (p < 0.0001). KCM decreased the initial clot formation time by about 1.5 times in those on DTI (p = 0.043) and 2.5 times in those taking AP medication (p < 0.001). The most profound effect was seen in those on UH (no KCM 1,602 s vs. KCM 440 s; p < 0.001), VKA (no KCM 1,152 s vs. 232 s; p < 0.01), and Xa (no KCM 1,342 s vs. 287 s; p < 0.001). Analysis of other clot formation parameters revealed that KCM significantly improved the clot formation kinetics (CFT) only in patients taking Xa (p = 0.03). KCM improved maximum clot strength in patients on Xa inhibitors (p = 0.05). Patients on UH had a larger effect size with an increase in clot strength from 24.35 mm to 43.35 mm whereas those on Xa had an increase of 38.7 mm to 49.85 mm. CONCLUSION: In this in vitro analysis, the addition of KCM to the blood of patients taking any of these anticoagulation medications significantly improved the time to initial clot formation, indicating that kaolin-based hemostatic dressings will be effective in initiating clot formation in patients on anticoagulants. LEVEL OF EVIDENCE: Therapeutic, level IV.

Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke).

BACKGROUND AND PURPOSE: We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients. METHODS: Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 µg/kg bolus) followed by infusion of either 1 (low dose) or 3 µg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0). RESULTS: Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively. CONCLUSIONS: In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.

Use of an argatroban-based purge solution in a percutaneous ventricular assist device.

PURPOSE: The use of an argatroban-based percutaneous ventricular assist device (pVAD) purge solution in a patient with suspected heparin-induced thrombocytopenia (HIT) is described. SUMMARY: A 70-year-old woman in cardiogenic shock was admitted to a coronary care unit after being discovered unresponsive at home. A transthoracic echocardiogram revealed a low ejection fraction and findings consistent with takotsubo cardiomyopathy. Administration of multiple inotropes and vasopressors was initially required for hemodynamic support. The patient was implanted with an Impella pVAD (Abiomed, Inc., Danvers, MA) using a heparin-based purge solution; an i.v. heparin infusion was initiated for supplemental systemic anticoagulation. Over the next 24 hours, the patient's platelet count decreased from 168,000 to 37,000 cells/µL. Given a differential diagnosis that included HIT, the patient was transitioned to an argatroban-based purge solution. Due to prolonged activated partial thromboplastin times, a systemic argatroban infusion was not initiated, and the patient remained fully anticoagulated throughout pVAD support with only the argatroban-based purge solution. An HIT antibody test was negative. On hospitalization day 9 (day 6 of pVAD support with argatroban use), the patient became hemodynamically stable and was weaned off pVAD support. Three days later, the platelet count had recovered to 117,000 cells/µL (from a nadir of 21,000 cells/µL). During pVAD support, the patient developed hemolytic anemia with minimal bleeding complications. CONCLUSION: Argatroban was used as a purge solution anticoagulant in a patient with an Impella pVAD and found to be a safe and effective alternative to heparin.

High-dose argatroban therapy for stroke: novel treatment for delayed treatment and the recanalization mechanism.

BACKGROUND: There has been little effective treatment in patients with cerebral infarction at >24 hours after onset. We assessed the effects of high-dose argatroban therapy in delayed administration, and investigated the mechanism based on our clinical findings. METHODS: Argatroban 30 mg was first administered for 15 minutes intravenously, and then 90 mg for 60 minutes followed by 60 mg for 60 minutes were infused continuously. The change of vascular obstruction caused by the treatment was assessed with magnetic resonance angiography. RESULTS: In 4 patients studied, high-dose argatroban resulted in 100% recanalization of occluded vessels (5/5), even though argatroban was administrated >24 hours after onset. On the other hand, when an inadequate dose of argatroban was administered, a hemorrhage was identified. This supports our hypothesis that high-dose argatroban promotes recanalization by deactivating thrombin and exerting an anticoagulant effect on the vascular endothelium. CONCLUSIONS: High-dose argatroban is an effective treatment for cerebral infarction and offers a novel therapeutic approach for delayed hospitalized patients at >24 hours after onset. Additional studies are necessary to identify the cellular and molecular mechanisms and determine the adequate dose in order to reduce risks of complication.

Alternative anticoagulation during cardiovascular procedures in pediatric patients with heparin-induced thrombocytopenia.

Patients with heparin-induced thrombocytopenia (HIT) that require anticoagulation for cardiovascular procedures represent a challenging and high-risk group. Bivalirudin and argatroban have been successfully used as alternative anticoagulants in adult patients with HIT. There have been few experiences published involving the pediatric population and controversy exists regarding the properties and optimal dosing of these drugs. This report describes the experience of managing two pediatric patients with HIT that underwent cardiovascular procedures requiring anticoagulation. Bivalirudin was used in both cases for anticoagulation during cardiopulmonary bypass, while argatroban was used without complications during cardiac catheterization. A description of perfusion and anticoagulation protocols is included.

High-dose argatroban for treatment of heparin-induced thrombocytopenia with thrombosis: a case report and review of laboratory considerations.

PURPOSE: A case report describing high-dose argatroban for the treatment of heparin-induced thrombocytopenia (HIT) with thrombosis and associated considerations in interpreting laboratory monitoring data are presented. SUMMARY: A 51-year-old woman with an extensive history of coronary artery disease arrived at the emergency department with complaints of chest pain. The patient was admitted, and coronary artery bypass graft surgery was ultimately performed. The patient had a baseline platelet count of 177,000 cells/µL. During hospitalization, the patient received heparin, and her platelet count dropped to 12,000 cells/µL 13 days after the initiation of heparin. The patient developed swelling around a peripherally inserted central catheter and later developed deep vein thrombosis. An argatroban infusion of 2 µg/kg/min was initiated, with a target activated partial thromboplastin time (aPTT) of 40-80 seconds. After 5 days of therapy, the patient had increased swelling in her right arm and an aPTT of 56 seconds. Her goal aPTT was subsequently increased. Six days later, the patient developed a left-lower-extremity DVT despite aPTTs within the goal range. A new aPTT target of >75 seconds was set. The infusion rate was increased to 15.5 µg/kg/min to attain the target aPTT. Results of an in vitro test led to an alternative interpretation of aPTT and International Normalized Ratio values that aided in the monitoring of argatroban during the high-dose infusion. CONCLUSION: A patient with HIT with thrombosis was successfully treated with unusually high dosages of argatroban and may have had serum argatroban concentrations exceeding what has commonly been thought to be the therapeutic range.

[Bilateral cerebellar infarction caused by intracranial dissection of the vertebral artery after long periods of "Shiatsu"].

For five years, a 56-year-old woman had undergone "Shiatsu" (a technique that uses fingers and the palm of the hand to apply pressure to particular sections of the body's surface to correct neck stiffness and body imbalances in order to maintain and promote health). She suddenly developed neck pain, dizziness, dysphagia, and speech and gait disturbances during treatment. A neurological examination detected bradylalia and truncal and mild bilateral limb ataxia of the cerebellar type. Diffusion-weighted brain MRI showed multiple hyperintense signal lesions at the bilateral cerebellar hemisphere in the posterior inferior cerebellar artery territory. Three-dimensional computed tomographic angiography (3D-CTA) revealed irregular stenosis of the intracranial right vertebral artery (string sign). Dissection of the intracranial portion of the vertebral artery owing to trauma is rare. Physicians need to be aware of patients who have acute dissecting infarction after long periods of repeated trivial pressure such as "Shiatsu". 3D-CTA is a very useful diagnostic procedure for arterial dissection.

Pharmacokinetics of cycloalliin, an organosulfur compound found in garlic and onion, in rats.

Cycloalliin, an organosulfur compound found in garlic and onion, has been reported to exert several biological activities and also to remain stable during storage and processing. In this study, we investigated the pharmacokinetics of cycloalliin in rats after intravenous or oral administration. Cycloalliin and its metabolite, (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid, in plasma, urine, feces, and organs was determined by a validated liquid chromatography-mass spectrometry method. When administered intravenously at 50 mg/kg, cycloalliin was rapidly eliminated from blood and excreted into urine, and its total recovery in urine was 97.8% +/- 1.3% in 48 h. After oral administration, cycloalliin appeared rapidly in plasma, with a tmax of 0.47 +/- 0.03 h at 25 mg/kg and 0.67 +/- 0.14 h at 50 mg/kg. Orally administered cycloalliin was distributed in heart, lung, liver, spleen, and especially kidney. The Cmax and AUC0-inf values of cycloalliin at 50 mg/kg were approximately 5 times those at 25 mg/kg. When administered orally at 50 mg/kg, cycloalliin was excreted into urine (17.6% +/- 4.2%) but not feces. However, the total fecal excretion of (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was 67.3% +/- 5.9% (value corrected for cycloalliin equivalents). In addition, no (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was detected in plasma (<0.1 microg/mL), and negligible amounts (1.0% +/- 0.3%) were excreted into urine. In in vitro experiments, cycloalliin was reduced to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid during anaerobic incubation with cecal contents of rats. These data indicated that the low bioavailability (3.73% and 9.65% at 25 and 50 mg/kg, respectively) of cycloalliin was due mainly to reduction to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid by the intestinal flora and also poor absorption in the upper gastrointestinal tract. These findings are helpful for understanding the biological effects of cycloalliin.

Direct thrombin inhibitors are not equally effective in vivo against arterial thrombosis: in vivo evaluation of DuP714 and argatroban in a porcine angioplasty model and comparison to r-hirudin.

BACKGROUND: Qualitative differences in antithrombotic efficacy between thrombin inhibitors may be explained by the affinity for which they bind thrombin. This affinity is inversely proportional to the inhibitory constant for the agent (Ki). Thrombin inhibitors, DuP714 (Ki=10(-11)) and argatroban (Ki=10(-8)), were compared to our previous studies with r-hirudin (Ki=10(-13)). METHODS AND RESULTS: Prior to balloon angioplasty, thirty pigs randomly received DuP714 (0.1 mg/kg bolus and 0.6 mg/kg/h infusion; n=8), argatroban (0.2 mg/kg/min. continuous infusion; n=9), or saline (n=17). Injured arterial segments were measured for (111)In-platelet and 125I-fibrin(ogen) deposition and the incidence of macroscopic thrombus. In DuP714-treated animals, platelet and fibrin(ogen) deposition were significantly lower than controls in both carotid (10+/-2 vs. 62+/-18 and 20+/-4 vs. 74+/-6) and coronary (10+/-4 vs. 160+/-63 and 17+/-3 vs. 86+/-22) arteries (p<0.005). In contrast, platelet and fibrin(ogen) deposition were similar when comparing argatroban to saline in carotid (41+/-20 vs. 40+/-9 and 71+/-5 vs. 49+/-7) and coronary (92+/-33 vs. 151+/-45 and 114+/-37 vs. 89+/-38) arteries (p=0.82 and 0.38, respectively). Compared to argatroban, fibrin(ogen) (p<0.001) and coronary platelet deposition (p<0.05) were significantly reduced in animals treated with DuP714 with no significant difference in carotid platelet deposition (p=0.10). Neither inhibitor prevented macroscopic thrombosis. In previous studies with r-hirudin in this model, platelet deposition was limited to a monolayer with complete inhibition of macroscopic thrombus. CONCLUSIONS: Direct thrombin inhibitors do not equally prevent arterial thrombosis. Qualitative differences may be explained in part by the affinity for which they bind thrombin.

Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study.

BACKGROUND AND PURPOSE: Direct thrombin inhibitors, including argatroban, represent an anticoagulant class distinct from heparins. We investigated the safety of 2 levels of argatroban anticoagulation in acute ischemic stroke. METHODS: This multicenter, randomized, double-blinded, placebo-controlled study included 171 patients with acute (< or =12 hours from onset) stroke and National Institutes of Health Stroke Scale (NIHSS) scores of 5 to 22. Patients received continuous intravenous argatroban (100 microg/kg bolus) at 3 microg/kg per minute (n=59) or 1 microg/kg per minute (n=58), respectively, adjusted to target activated partial thromboplastin times (aPTTs) 2.25x and 1.75x baseline or placebo (n=54) for 5 days. The primary outcome was symptomatic intracranial hemorrhage (ICH) at 30 days. RESULTS: Baseline characteristics including neurologic deficits (median NIHSS score 9) were comparable between groups. Argatroban at mean doses of 2.7 and 1.2 microg/kg per minute increased aPTTs significantly (P<0.001), with mean aPTTs at or near target values throughout infusion. Symptomatic ICH was not significantly different between groups (high-dose argatroban, 5.1%; low-dose argatroban, 3.4%; placebo, 0%; P> or =0.18), with 3 events during argatroban infusion and 2 events > or =7 days after stopping infusion. No significant between-group differences occurred in asymptomatic ICH (7 events), major systemic hemorrhage (no event), or 90-day mortality (13.4% overall). CONCLUSIONS: In this first North American randomized, double-blinded, placebo-controlled study of direct thrombin inhibition in acute ischemic stroke, argatroban at each dose evaluated significantly prolonged aPTTs without increasing ICH or major bleeding. These results suggest that argatroban provides safe anticoagulation in acute ischemic stroke, warranting future studies powered to evaluate its efficacy and more precisely estimate event rates.

The effect of dietary bacillus natto productive protein on in vivo endogenous thrombolysis.

The influence of dietary bacillus natto productive protein (BNPP) on endogenous thrombolysis was investigated in the rat. Animals were given a standard feed for 14 weeks, to which 0.2 or 1% BNPP was added. Thrombolysis was evaluated using an He-Ne laser-induced thrombosis model in mesenteric microvessels. Changes in thrombus volume, reflecting thrombolysis, decreased to 82% of the initial value in the control group. In contrast, the thrombus volume decreased to 67% in the animals fed 0.2% BNPP, and decreased to 51% in the group given 1% BNPP. The extent of thrombolysis in the 1% BNPP group was equivalent to that seen in animals treated with a bolus intravenous infusion of 0.2 mg/kg tissue plasminogen activator. The results demonstrated that the dietary administration of BNPP enhanced endogenous thrombolysis in a dose-dependent manner. Argatroban (2 mg/kg/h) enhanced endogenous fibrinolysis only in control animals, but not in the BNPP groups. The results support the suggestion that dietary supplementation with BNPP may provide a simple means to promote fibrinolysis not only in the treatment of thromboembolism but also in the prevention of venous occlusion.

Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Studies indicate that thrombin plays an important role in intracerebral hemorrhage (ICH)-induced edema formation. Although thrombin is produced as the blood clots, it may be bound to fibrin and only gradually released from the clot. The time window for administration of a thrombin inhibitor to reduce ICH-induced edema is unknown. Whether this time window extends beyond the period when a thrombin inhibitor might exacerbate rebleeding is also unknown. METHODS: This study examines (1) whether argatroban, an inhibitor of both free and fibrin-bound thrombin, can reduce edema formation after intracerebral infusion of 100 micro L of blood in the rat; (2) the therapeutic time window for argatroban; and (3) whether argatroban promotes rebleeding in a model in which ICH was induced by intracerebral injection of collagenase. RESULTS: Intracerebral infusion of blood caused a marked increase in perihematomal water content. Intracerebral injection of argatroban 3 hours after ICH caused a significant reduction in edema measured at 48 hours (80.9+/-1.0% versus 82.6+/-0.8%; P<0.01). The systemic administration of high-dose argatroban (0.9 mg/h) starting 6 hours after ICH also significantly reduced edema (80.3+/-1.1% versus 82.0+/-1.3% in vehicle controls; P<0.05). There was no protection when the onset of argatroban administration was delayed to 24 hours after ICH or if a lower dose of argatroban (0.3 mg/h) was used. Argatroban did not increase collagenase-induced hematoma volume when given into the clot after 3 hours or given systemically at 6 hours. CONCLUSIONS: Our data suggest that argatroban may be an effective therapy for ICH-induced edema.

Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that can lead to limb- and life-threatening thrombosis. Argatroban, a small synthetic molecule (Argatroban; GlaxoSmithKline, Philadelphia, PA), and lepirudin, a protein of non-human origin (Refludan; Aventis, Bridgewater, NJ), are direct thrombin inhibitors that have been used successfully for anticoagulant therapy in HIT patients. It has been reported that between 44-74% of lepirudin-treated HIT patients develop drug-specific antibodies that either enhance or suppress the anticoagulant activity of lepirudin. By contrast, there have been no reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect in clinical trials, including those in HIT patients, or in postmarketing safety surveillance of over 4,800 patients treated in Japan. To confirm the lack of antibodies in argatroban-treated patients with HIT, we examined plasma for anticoagulant-altering activity and reviewed dosing patterns of re-exposed patients. Paired, pre-therapy and post-therapy (> or =7 days) plasma pools exhibited comparable in vitro anticoagulant responses (aPTT and antithrombin activity) to argatroban supplementation. Argatroban at 5 microg/mL similarly prolonged aPTTs of normal plasma pretreated with IgG isolated from pre-therapy versus post-therapy plasma (P>0.6). In trials, mean argatroban doses during initial therapy versus re-exposure were not different among individuals anticoagulated for the treatment or prophylaxis of thrombosis (P=0.60) or during percutaneous coronary interventions (P=0.79), with no discernable pattern of suppression or enhancement of argatroban anticoagulation. Consistent with the lack of reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect across clinical trials and post-marketing safety surveillance, these data support the lack of anti-argatroban antibodies that affect drug activity in argatroban-treated HIT patients.

Anticoagulant activity and pharmacokinetic properties of a sub-cutaneously administered mixed micellar formulation of argatroban in experimental animals.

We have studied the anticoagulant properties of a novel mixed micellar formulation containing 14 mg/ml argatroban administered by the sub-cutaneous (s.c.) route to rats, rabbits, dogs and primates. Blood samples were taken at various times post-treatment for the determination of the thrombin time (TT), Ecarin clotting time (ECT) and the activated partial thromboplastin time (aPTT). Plasma levels of argatroban were determined in the dog and primate. Mixed micelles alone (0.15 M sodium glycocholate and 0.15 M egg lecithin) were without effect on the clotting parameters. The mixed micellar formulation of argatroban dose-dependently increased all three clotting parameters in the rat (1-4 mg/kg), the rabbit (1 and 2 mg/kg), the dog (1 and 2 mg/kg) and the primate (0.25 and 0.5 mg/kg). In each case the TT was the most sensitive parameter, followed by the ECT and the aPTT. The duration of action of argatroban in each species was dose dependent and varied from 3 h in the rat to 6 h in the dog. In the latter, the mixed micelle formulation had a significantly increased plasma half-life and mean residence time without affecting the overall area under the curve. The increases in the clotting time were strongly correlated with the plasma levels of argatroban and were linear across the range of concentrations obtained in the dog and the primate, although the aPTT plasma concentration response curve was very flat. Species differences were noted between the increase in clotting time for a given plasma concentration, with the primate being more sensitive than the dog (e.g. 4.7 times more so in terms of the ECT). Thus, a mixed micellar formulation of argatroban, which markedly enhances its solubility, could be useful as a potential anticoagulant for sub-cutaneous administration.

Activity of a sub-cutaneously administered novel mixed micellar formulation of argatroban in rat and rabbit models of venous thrombosis.

We studied the antithrombotic activity of a mixed micellar formulation containing 14 mg/ml argatroban administered by the subcutaneous (s.c.) route in rat and rabbit models of venous thrombosis. The effects on bleeding time in the rat tail transection bleeding time test were also studied. In a tissue factor-dependent arterio-venous shunt model, argatroban treatment led to dose-dependent reduction in thrombus weight with an estimated ID50 of 1.8 mg/kg s.c. In the same model, heparin had an estimated ID50 of 179 IU/kg. The antithrombotic activity of argatroban was accompanied by increases in the thrombin and ecarin clotting times but not the aPTT, whereas heparin increased the thrombin time and aPTT but not the ecarin clotting times. Argatroban also inhibited thrombus formation in a rabbit model of thromboplastin + stasis induced thrombosis in the rabbit jugular vein with an estimated ID50 of 1 mg/kg s.c. When tested in the rat tail transection bleeding time test, the mixed micellar formulation of argatroban caused significant increases in the bleeding time as from 8 mg/kg s.c., while heparin significantly increased the bleeding time at 800 U/kg. Mixed micellar argatroban appears to have a superior safety margin to heparin in terms of antithrombotic efficacy and bleeding risk. Thus, a mixed micellar formulation of argatroban, which markedly enhances its solubility, could be useful as a potential antithrombotic agent for subcutaneous administration.

Local antithrombotic therapy using a novel porous balloon catheter.

The efficacy of local treatment of thrombosis with low-dose antithrombotic drugs (heparin: 30 U/kg, or argatroban: 0.02 mg/kg) was investigated using a novel porous balloon catheter. This novel balloon catheter can deliver drug into arterial walls without causing vascular trauma. Thrombus formation was significantly inhibited in balloon-injured and locally-treated iliac arteries compared with control balloon-injured arteries in 12 dogs. In the systemic high-dose delivery group (ten times as high as the low dose), thrombus formation in injured arteries was significantly less than that of controls in 7 dogs. Low-dose systemic delivery was not effective at inhibiting this thrombus formation. Thus, local treatment with an antithrombotic drug using this novel porous balloon catheter can prevent thrombosis without influencing systemic coagulability.

A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study.

OBJECTIVES: This study examined the effect of a small-molecule, direct thrombin inhibitor, argatroban, on reperfusion induced by tissue plasminogen activator (TPA) in patients with acute myocardial infarction (AMI). BACKGROUND: Thrombin plays a crucial role in thrombosis and thrombolysis. In vitro and in vivo studies have shown that argatroban has advantages over heparin for the inhibition of clot-bound thrombin and for the enhancement of thrombolysis with TPA. METHODS: One hundred and twenty-five patients with AMI within 6 h were randomized to heparin, low-dose argatroban or high-dose argatroban in addition to TPA. The primary end point was the rate of thrombolysis in myocardial infarction (TIMI) grade 3 flow at 90 min. RESULTS: TIMI grade 3 flow was achieved in 42.1% of heparin, 56.8% of low-dose argatroban (p = 0.20 vs. heparin) and 58.7% of high-dose argatroban patients (p = 0.13 vs. heparin). In patients presenting after 3 h, TIMI grade 3 flow was significantly more frequent in high-dose argatroban versus heparin patients: 57.1% versus 20.0% (p = 0.03 vs. heparin). Major bleeding was observed in 10.0% of heparin, and in 2.6% and 4.3% of low-dose and high-dose argatroban patients, respectively. The composite of death, recurrent myocardial infarction, cardiogenic shock or congestive heart failure, revascularization and recurrent ischemia at 30 days occurred in 37.5% of heparin, 32.0% of low-dose argatroban and 25.5% of high-dose argatroban patients (p = 0.23). CONCLUSIONS: Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation. The incidences of major bleeding and adverse clinical outcome were lower in the patients receiving argatroban.